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Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines.

Chen CC, Lau LF - J Cell Commun Signal (2009)

Bottom Line: Mechanistically, CCNs function through integrin alpha(6)beta(1) and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism.Mutant CCN1 proteins defective for binding alpha(6)beta(1)-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines.Further, knockin mice that express an alpha(6)beta(1)-HSPG-binding defective CCN1 are blunted in TNFalpha- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607 USA.

ABSTRACT
Recent studies have revealed an unexpected synergism between two seemingly unrelated protein families: CCN matricellular proteins and the tumor necrosis factor (TNF) family of cytokines. CCN proteins are dynamically expressed at sites of injury repair and inflammation, where TNF cytokines are also expressed. Although TNFalpha is an apoptotic inducer in some cancer cells, it activates NFkappaB to promote survival and proliferation in normal cells, and its cytotoxicity requires inhibition of de novo protein synthesis or NFkappaB signaling. The presence of CCN1, CCN2, or CCN3 overrides this requirement and unmasks the apoptotic potential of TNFalpha, thus converting TNFalpha from a proliferation-promoting protein into an apoptotic inducer. These CCN proteins also enhance the cytotoxicity of other TNF cytokines, including LTalpha, FasL, and TRAIL. Mechanistically, CCNs function through integrin alpha(6)beta(1) and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism. Mutant CCN1 proteins defective for binding alpha(6)beta(1)-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines. Further, knockin mice that express an alpha(6)beta(1)-HSPG-binding defective CCN1 are blunted in TNFalpha- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes. These findings implicate CCN proteins as contextual regulators of the inflammatory response by dictating or enhancing the cytotoxicity of TNFalpha and related cytokines.

No MeSH data available.


Related in: MedlinePlus

TNFα induced signaling. TNFα is capable of inducing both pro-survival and pro-apoptotic signaling through its receptor TNFR1. Formation of complex 1 leads to activation of NFκB and its downstream effectors, while complex II can trigger apoptosis through activation of the caspase cascade. The apoptotic pathway is blocked by c-FLIP, which is targeted for degradation by the ubiquitin ligase ITCH and apoptosis can proceed if JNK activation is sustained (Chang et al. 2006). Signaling molecules in green provide survival functions, while those in red contribute to apoptosis. Those in yellow promote apoptosis only when superactivated under certain contexts
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Fig3: TNFα induced signaling. TNFα is capable of inducing both pro-survival and pro-apoptotic signaling through its receptor TNFR1. Formation of complex 1 leads to activation of NFκB and its downstream effectors, while complex II can trigger apoptosis through activation of the caspase cascade. The apoptotic pathway is blocked by c-FLIP, which is targeted for degradation by the ubiquitin ligase ITCH and apoptosis can proceed if JNK activation is sustained (Chang et al. 2006). Signaling molecules in green provide survival functions, while those in red contribute to apoptosis. Those in yellow promote apoptosis only when superactivated under certain contexts

Mentions: When TNFα engages its cell surface receptor TNFR1, the death domain in the receptor cytoplasmic tail recruits the adaptor protein TRADD, which further recruits RIP and TRAF2 that participate in the activation of NFκB and JNK (Fig. 3). The RIP, TRAF2, and TRADD complex (complex I) subsequently dissociates from the receptor and recruits FADD and procaspase-8/-10 into a secondary complex (complex II) in which activation of procaspase-8/-10 occurs (Muppidi et al. 2004; Bertazza and Mocellin 2008). Whereas caspases-8/-10 can directly activate caspase-3 by proteolysis to trigger apoptosis, in some cell types caspase-8 cleaves and activates the BH3-only protein Bid, leading to cytochrome c release from the mitochondria and amplification of the apoptotic signal. Cytoplasmic cytochrome c complexes with Apaf-1 and activates caspase-9, which further activates caspase-3 to trigger apoptosis.Fig. 3


Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines.

Chen CC, Lau LF - J Cell Commun Signal (2009)

TNFα induced signaling. TNFα is capable of inducing both pro-survival and pro-apoptotic signaling through its receptor TNFR1. Formation of complex 1 leads to activation of NFκB and its downstream effectors, while complex II can trigger apoptosis through activation of the caspase cascade. The apoptotic pathway is blocked by c-FLIP, which is targeted for degradation by the ubiquitin ligase ITCH and apoptosis can proceed if JNK activation is sustained (Chang et al. 2006). Signaling molecules in green provide survival functions, while those in red contribute to apoptosis. Those in yellow promote apoptosis only when superactivated under certain contexts
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2821476&req=5

Fig3: TNFα induced signaling. TNFα is capable of inducing both pro-survival and pro-apoptotic signaling through its receptor TNFR1. Formation of complex 1 leads to activation of NFκB and its downstream effectors, while complex II can trigger apoptosis through activation of the caspase cascade. The apoptotic pathway is blocked by c-FLIP, which is targeted for degradation by the ubiquitin ligase ITCH and apoptosis can proceed if JNK activation is sustained (Chang et al. 2006). Signaling molecules in green provide survival functions, while those in red contribute to apoptosis. Those in yellow promote apoptosis only when superactivated under certain contexts
Mentions: When TNFα engages its cell surface receptor TNFR1, the death domain in the receptor cytoplasmic tail recruits the adaptor protein TRADD, which further recruits RIP and TRAF2 that participate in the activation of NFκB and JNK (Fig. 3). The RIP, TRAF2, and TRADD complex (complex I) subsequently dissociates from the receptor and recruits FADD and procaspase-8/-10 into a secondary complex (complex II) in which activation of procaspase-8/-10 occurs (Muppidi et al. 2004; Bertazza and Mocellin 2008). Whereas caspases-8/-10 can directly activate caspase-3 by proteolysis to trigger apoptosis, in some cell types caspase-8 cleaves and activates the BH3-only protein Bid, leading to cytochrome c release from the mitochondria and amplification of the apoptotic signal. Cytoplasmic cytochrome c complexes with Apaf-1 and activates caspase-9, which further activates caspase-3 to trigger apoptosis.Fig. 3

Bottom Line: Mechanistically, CCNs function through integrin alpha(6)beta(1) and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism.Mutant CCN1 proteins defective for binding alpha(6)beta(1)-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines.Further, knockin mice that express an alpha(6)beta(1)-HSPG-binding defective CCN1 are blunted in TNFalpha- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607 USA.

ABSTRACT
Recent studies have revealed an unexpected synergism between two seemingly unrelated protein families: CCN matricellular proteins and the tumor necrosis factor (TNF) family of cytokines. CCN proteins are dynamically expressed at sites of injury repair and inflammation, where TNF cytokines are also expressed. Although TNFalpha is an apoptotic inducer in some cancer cells, it activates NFkappaB to promote survival and proliferation in normal cells, and its cytotoxicity requires inhibition of de novo protein synthesis or NFkappaB signaling. The presence of CCN1, CCN2, or CCN3 overrides this requirement and unmasks the apoptotic potential of TNFalpha, thus converting TNFalpha from a proliferation-promoting protein into an apoptotic inducer. These CCN proteins also enhance the cytotoxicity of other TNF cytokines, including LTalpha, FasL, and TRAIL. Mechanistically, CCNs function through integrin alpha(6)beta(1) and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism. Mutant CCN1 proteins defective for binding alpha(6)beta(1)-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines. Further, knockin mice that express an alpha(6)beta(1)-HSPG-binding defective CCN1 are blunted in TNFalpha- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes. These findings implicate CCN proteins as contextual regulators of the inflammatory response by dictating or enhancing the cytotoxicity of TNFalpha and related cytokines.

No MeSH data available.


Related in: MedlinePlus